Coatings containing polycationic peptides for cardiovascular therapy

ABSTRACT

Coatings for implantable medical devices and methods for fabricating the same are disclosed. The coatings include a region containing a polycationic peptide, such as, for example, the polycationic peptide known as R7.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to the field of medical devices, especiallydevices used for delivery of drugs. Particularly, this invention isdirected to coatings for drug delivery devices, such as drug elutingvascular stents. More particularly, this invention is directed tocoatings which include polycationic peptides such as polymers and/oroligomers of L-arginine.

2. Description of the State of the Art

Percutaneous transluminal coronary angioplasty (PTCA) is a procedure fortreating heart disease. A catheter assembly having a balloon portion isintroduced percutaneously into the cardiovascular system of a patientvia the brachial or femoral artery. The catheter assembly is advancedthrough the coronary vasculature until the balloon portion is positionedacross the occlusive lesion. Once in position across the lesion, theballoon is inflated to a predetermined size to radially compress againstthe atherosclerotic plaque of the lesion to remodel the lumen wall. Theballoon is then deflated to a smaller profile to allow the catheter tobe withdrawn from the patient's vasculature.

A problem associated with the above procedure includes formation ofintimal flaps or torn arterial linings which can collapse and occludethe conduit after the balloon is deflated. Moreover, thrombosis andrestenosis of the artery may develop over several months after theprocedure, which may require another angioplasty procedure or a surgicalby-pass operation. To reduce the partial or total occlusion of theartery by the collapse of arterial lining and to reduce the chance ofthe development of thrombosis and restenosis, a stent is implanted inthe lumen to maintain the vascular patency.

Stents are used not only as a mechanical intervention but also as avehicle for providing biological therapy. As a mechanical intervention,stents act as scaffoldings, functioning to physically hold open and, ifdesired, to expand the wall of the passageway. Typically, stents arecapable of being compressed, so that they can be inserted through smallvessels via catheters, and then expanded to a larger diameter once theyare at the desired location. Examples in patent literature disclosingstents which have been applied in PTCA procedures include stentsillustrated in U.S. Pat. No. 4,733,665 issued to Palmaz, U.S. Pat. No.4,800,882 issued to Gianturco, and U.S. Pat. No. 4,886,062 issued toWiktor.

Biological therapy can be achieved by medicating the stents. Medicatedstents provide for the local administration of a therapeutic substanceat the diseased site. In order to provide an efficacious concentrationto the treated site, systemic administration of such medication oftenproduces adverse or toxic side effects for the patient. Local deliveryis a preferred method of treatment in that smaller total levels ofmedication are administered in comparison to systemic dosages, but areconcentrated at a specific site. Local delivery thus produces fewer sideeffects and achieves more favorable results. One proposed method formedicating stents involves the use of a polymeric carrier coated ontothe surface of a stent. A solution which includes a solvent, a polymerdissolved in the solvent, and a therapeutic substance dispersed in theblend is applied to the stent. The solvent is allowed to evaporate,leaving on the stent surface a coating of the polymer and thetherapeutic substance impregnated in the polymer.

Local administration of therapeutic agents via stents has shown somefavorable results in reducing restenosis. However, development ofrestenosis remains a persistent problem which has not been significantlyalleviated by therapeutic substances which are currently used in themarket. Accordingly, there is a great need for better and more effectivetherapeutic compositions, and methods of administering the compositions,for the effective treatment of restenosis.

SUMMARY

A coating for an implantable medical device, such as a stent, isdisclosed. The coating comprises a region including a polycationicpeptide and a region free from any polycationic peptides. Thepolycationic peptide can be poly(L-arginine), poly(D-arginine),poly(D,L-arginine), poly(L-lysine), poly(D-lysine),poly(δ-guanidino-α-aminobutyric acid), and a racemic mixture ofpoly(L-arginine) or poly(D-arginine). In one embodiment, the regionincluding the polycationic peptide includes a hydrogel containing thepolycationic peptide. The hydrogel can be fabricated of substancescomprising carboxylated hydrocarbons, polycationic compounds,polyanionic compounds and mixtures thereof. In one embodiment, theregion free from the polycationic peptide is positioned on the surfaceof the device and beneath the region including the polycationic peptide.In an alternative embodiment, the polycationic peptide can beencapsulated in particles in the coating.

A method for fabricating a coating for an implantable medical device,such as a stent, is also disclosed. The method comprises forming acoating on the device, the coating including a polycationic peptide; andtreating the coating with a stimulus for enriching a region close to theouter surface of the coating with the polycationic peptide. In oneembodiment, the treatment of the coating includes subjecting the deviceto a humid environment at a selected temperature, for example about 50°C. at a humidity of about 100%. In another embodiment, the treatment caninclude subjecting the device to an electronic beam or to autoclaving.

A method of modifying a coating for an implantable medical device isdisclosed. The method comprises exposing the coating, including apolycationic peptide to ethylene oxide at a selected temperature andconjugating poly(ethylene glycol) to the coating.

A method of fabricating a coating for a medical device is disclosed. Themethod comprises forming a coating on the device, the coating includinga polycationic peptide, and causing some of the bonds of the peptide tobe cleaved for increasing the population of the peptide in the coating.

A stent comprising a coating is also disclosed wherein the coatingincludes a peptide such that the population of the peptide is greater inthe outermost region of the coating.

A method of fabricating a coated stent is also disclosed, comprisingforming a coating on the stent wherein the coating includes a regioncontaining a peptide and a region free from any peptides.

DETAILED DESCRIPTION

The stent coating according to the embodiments of the present inventionmay have any one or combination of the following layers or regions inaddition to the reservoir layer containing a therapeutic substance: aprimer layer, a topcoat layer, and a finishing coat layer. The optionalfinishing coat layer may also include a drug or a therapeutic substance.The reservoir layer can be applied directly onto the stent surface, oroptionally on the primer layer. The optional finishing coat layer can beapplied on the topcoat layer and, when present, can be the outermostregion of the stent coating. Subsequent to the implantation of thestent, the reservoir layer gradually releases the therapeutic substance.

One example of a drug or therapeutic substance that can be used is apolycationic peptide or a mixture of several polycationic peptides.Representative examples of suitable polycationic peptides includepoly(L-arginine), poly(D-arginine), poly(D,L-arginine), poly(L-lysine),poly(D-lysine), poly(δ-guanidino-α-aminobutyric acid), racemic mixturesof poly(L-arginine) and poly(D-arginine), chitosan, and mixturesthereof. L-arginine, also known as R or 2-amino-5-guanidinovaleric acid,is an amino acid having a formula NH═C(NH₂)—NH—CH₂—CH₂—CH₂—CH(NH₂)—COOH.Polymers and/or oligomers of L-, D-, and/or D, L-arginine that can beused are referred to in the present application as “PArg” and comprise aplurality of repeating monomeric amino acid units connected with peptidebonds. PArg has a general formulaH[NH—CHX—CO]_(p)—OH  (I)where “p” can be within a range of 5 and 1,000, or, within a range ofbetween 6 and 20. For example, a heptamer (R7) (p=7), or a nonamer (R9)(p=9), can be used.

In formula (I), “X” represents 1-guanidinopropyl radical having thestructure —CH₂—CH₂—CH₂—NH—C(NH₂)═NH. The terms “polymers and/oroligomers of D-, L-, and/or D, L-arginine,” “poly(L-arginine),”“poly(D-arginine),” “poly(D,L-arginine),” and “PArg” used in the presentapplication are intended to include L-, D-, and/or D,L-arginine in bothits polymeric and oligomeric form.

Poly(ethylene-co-vinyl alcohol) (EVAL) is one example of a polymer thatcan be used for any of the coating layers. EVAL is a product ofhydrolysis of ethylene-vinyl acetate copolymers and has the generalformula —[CH₂—CH₂]_(m)—[CH₂—CH(OH)]_(n)—. EVAL may also include aterpolymer having up to about 5 molar % of units derived from styrene,propylene and other suitable unsaturated monomers. A brand of copolymerof ethylene and vinyl alcohol distributed commercially under the tradename EVAL by Aldrich Chemical Co. of Milwaukee, Wis., can be used.

Other examples of polymers that can be used include polyacrylates, suchas poly(butyl methacrylate) (PBMA), poly(ethyl methacrylate) (PEMA), andpoly(ethyl methacrylate-co-butyl methacrylate) [P(EMA-BMA)]; fluorinatedpolymers and/or copolymers, such as poly(vinylidene fluoride) (PVDF) andpoly(vinylidene fluoride-co-hexafluoro propene) (PVDF-HFP); and blendsof polyacrylates and fluorinated polymers and/or copolymers. One exampleof the blend of a polyacrylate and a fluorinated polymer that can beused can contain between about 10 and about 95% (mass) of thefluorinated polymer.

Representative examples of other suitable polymers includepoly(hydroxyvalerate), poly(L-lactic acid), polycaprolactone,poly(lactide-co-glycolide), poly(hydroxybutyrate),poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester,polyanhydride, poly(glycolic acid), poly(D,L-lactic acid), poly(glycolicacid-co-trimethylene carbonate), polyphosphoester, polyphosphoesterurethane, poly(amino acids), cyanoacrylates, poly(trimethylenecarbonate), poly(iminocarbonate), co-poly(ether-esters) (e.g. PEO/PLA),polyalkylene oxalates, polyphosphazenes, biomolecules (such as fibrin,fibrinogen, cellulose, starch, collagen and hyaluronic acid),polyurethanes, silicones, polyesters, polyolefins, polyisobutylene andethylene-alphaolefin copolymers, vinyl halide polymers and copolymers(such as polyvinyl chloride), polyvinyl ethers (such as polyvinyl methylether), polyvinylidene chloride, polyacrylonitrile, polyvinyl ketones,polyvinyl aromatics (such as polystyrene), polyvinyl esters (such aspolyvinyl acetate), copolymers of vinyl monomers with each other andolefins (such as ethylene-methyl methacrylate copolymers,acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl acetatecopolymers), polyamides (such as Nylon 66 and polycaprolactam), alkydresins, polycarbonates, polyoxymethylenes, polyimides, polyethers, epoxyresins, polyurethanes, rayon, rayon-triacetate, cellulose, celluloseacetate, cellulose butyrate, cellulose acetate butyrate, cellophane,cellulose nitrate, cellulose propionate, cellulose ethers, andcarboxymethyl cellulose.

A. A Solution or Suspension Method for Incorporating PArg into StentCoatings

The coating can be formed on the stent by dissolving the polymer in asolvent, or a mixture of solvents, and applying the resulting polymersolution on the stent by spraying or immersing the stent in thesolution. To incorporate PArg into the reservoir layer and/or theoptional finishing coat layer, PArg in a form of a solution can becombined with the polymer solution.

Representative examples of some solvents suitable for making the polymersolution include N,N-dimethylacetamide (DMAC), N,N-dimethylformamide(DMF), tethrahydrofurane (THF), cyclohexanone, xylene, toluene, acetone,i-propanol, methyl ethyl ketone, propylene glycol monomethyl ether,methyl butyl ketone, ethyl acetate, n-butyl acetate, and dioxane. Somesolvent mixtures can be used as well. Representative examples of themixtures include:

(1) DMAC and methanol (e.g., 50:50 by mass mixture);

(2) water, i-propanol, and DMAC (e.g., 10:3:87 by mass mixture);

(3) i-propanol, and DMAC (e.g., 80:20, 50:50, or 20:80 by massmixtures);

(4) acetone and cyclohexanone (e.g., 80:20, 50:50, or 20:80 by massmixtures);

(5) acetone and xylene (e.g. 50:50 by mass mixture); and

(6) acetone, FLUX REMOVER AMS, and xylene (e.g., 10:50:40 by massmixture).

FLUX REMOVER AMS is the trade name of a solvent manufactured by TechSpray, Inc. of Amarillo, Tex. comprising about 93.7% of a mixture of3,3-dichloro-1,1,1,2,2-pentafluoropropane and1,3-dichloro-1,1,2,2,3-pentafluoropropane, and the balance of methanol,with trace amounts of nitromethane. Those having ordinary skill in theart will select the solvent or a mixture of solvents suitable for aparticular polymer being dissolved.

Instead of introducing PArg in a solution, PArg can be introduced as acolloid system, such as a suspension in an appropriate solvent phase.The suspension can be mixed with a polymer solution. One example of thesolvent phase can be a mixture of water, i-propanol and DMAC, containingbetween about 3 and 6 mass % of water, between about 18 and 19% ofi-propanol, and the balance, DMAC solvent.

After the stent coating has been formed, the stent can then beadditionally treated to enrich the surface with PArg. Various techniquesof treatment can be used depending on the kind of PArg and whether afinishing coat layer is used.

In one embodiment, the coated stent can be exposed to the environment ofa humidifying chamber. This treatment is particularly useful for R7 orR9. The length of such treatment can be, for example, about 24 hours, ata temperature of about 50° C. and relative humidity of about 100%. Anycommercially available chamber can be used. As a result of the exposureof the stent to high humidity levels at elevated temperatures, theoutermost surface of the coating is enriched with the peptide (e.g., R7or R9).

If the finishing coat layer is not used, the stent can be treated afterthe reservoir layer containing the peptide (e.g., R7 or R9) has beenapplied, but prior to applying the topcoat layer. Consequently, as aresult of the treatment, the surface of the drug-polymer layer getsenriched with the R7 or R9, followed by fabrication of the topcoatlayer.

In another embodiment of the invention, the coated stent can be treatedwith high energy electronic beams. This method of treatment can be mosteffectively employed when the PArg is higher than nonamer, or in otherwords, in formula (I), p should be greater than about 20. For example,the PArg can have a weight-average molecular weight of about 5,000,corresponding to a “p” value of about 29. Under the influence of theelectronic beam, the peptide bonds of PArg undergo cleavage, causingde-polymerization of PArg. Consequently, the population of the peptide(e.g., R7 or R9) in the stent coating increases. The length of theelectronic beam treatment can be about 1 second. The standard equipmentused for sterilization of the stents can be used, with the electronicbeam having energy of about 2.5 MRad (25 kilograys).

Alternatively, instead of treatment with the electronic beam, the stentcan be treated by autoclaving. High pressure and temperature in theautoclave will also cause de-polymerization of PArg leading to theenrichment of the stent coating with the sub-population of R7 or R9. Theconditions of autoclaving will be selected by those having ordinaryskill in the art.

In accordance with yet another embodiment, the coated stent can besterilized at a high temperature, for example, above about 100° C.During sterilization, PArg contained in the outermost layer of the stentcoating can be exposed to ethylene oxide.

Under conditions of high temperature, the proton at the nitrogen atom ofthe peptide bond —NH—CO— of PArg will be activated and will attack theoxyran ring of ethylene oxide causing the ring to open forming anethylene glycol (—CH₂—CH₂—O—) moiety. As a result poly(ethylene glycol)(PEG) can be chemically bonded to the coating's surface. The path of thereaction can be shown as reaction (II):

The high temperature treatment in the presence of ethylene glycol thusmakes it possible to sterilize the stent and to simultaneously conjugatePEG, a biologically active substance, to the stent coating.

B. Incorporating PArg into Stent Coatings Using Hydrogels

PArg can be incorporated in the stent coating by using hydrogeltechnology. For example, a hydrogel can be prepared by mixing R7 andpoly(glutamic acid) (PGlA). A R7: PGlA ratio can be between about 1:1and 5:1. Instead of PGlA, other highly carboxylated hydrocarbons can beused in the alternative, for instance, polyalginate, sulfonated dextran,or mixtures thereof. A portion of PGlA or its alternatives can bereplaced with other polycationic or polyanionic compounds. Examples ofsuch polycationic or polyanionic compounds include PArg, polylysine,poly(dimethylaminoethyl methacrylate) (PDMAEM), poly(acrylic acid), andpolysaccharides.

The hydrogel containing R7 can be mixed with the polymer solutionforming the drug-polymer layer or the optional finishing coat layer. Thehydrogel can be used to cause endothelialization. Those having ordinaryskills in the art may also choose to use the hydrogel in applicationsnot involving stent coatings. Examples of such applications includeusing the hydrogel in tissue sealants, with biological adhesivesdesigned to accelerate healing, and with biocompatible viscosifiers suchas hyaluronic acid or carboxymethyl cellulose.

C. Incorporating PArg into Stent Coatings Using Micro- or Nanoparticles

PArg can be incorporated in the stent coating by being firstincorporated into particles of micron to sub-micron size (i.e., micro-or nanoparticles). For example, the particles can have diameter betweenabout 0.5 and 4.0 μm. The particles comprise a sphere-type outer shellmade of an encapsulating polymer and an inside space filled with PArg.The particles can be made by an emulsion method according to techniquesknown to those having ordinary skill in the art. Examples of suitableencapsulating polymers having varying rates of hydrolysis includepoly(glycolic acid) (PGA), poly(D-lactic acid) (PDLA), poly(L-lacticacid) (PLLA), poly(butylene terephthalate-co-ethylene glycol), PBT-PEG,and mixtures thereof.

The micro- or nanoparticles containing R7 can be suspended in thepolymer solution forming the drug-polymer layer and/or the finishingcoat layer and applied onto the stent. The peptide particles-to-polymerratio can be within a range of between about 1:5 and 1:10. When thestent is in contact with body fluids, the polymer forming the outershell of the particles will hydrolyze and degrade thus releasing thepeptide, such as the R7.

The polycationic peptides can be introduced alone or blended with otheractive agent(s). Generally speaking, the active agent can include anysubstance capable of exerting a therapeutic or prophylactic effect inthe practice of the present invention. Examples of agents includeantiproliferative substances such as actinomycin D, or derivatives andanalogs thereof. Synonyms of actinomycin D include dactinomycin,actinomycin IV, actinomycin II, actinomycin X₁, and actinomycin C₁. Theactive agent can also fall under the genus of antineoplastic,anti-inflammatory, antiplatelet, anticoagulant, antifibrin,antithrombin, antimitotic, antibiotic, antiallergic and antioxidantsubstances. Examples of such antineoplastics and/or antimitotics includepaclitaxel, docetaxel, methotrexate, azathioprine, vincristine,vinblastine, fluorouracil, doxorubicin hydrochloride, and mitomycin.Examples of such antiplatelets, anticoagulants, antifibrin, andantithrombins include sodium heparin, low molecular weight heparins,heparinoids, hirudin, argatroban, forskolin, vapiprost, prostacyclin andprostacyclin analogues, dextran, D-phe-pro-arg-chloromethylketone(synthetic antithrombin), dipyridamole, glycoprotein IIb/IIIa plateletmembrane receptor antagonist antibody, recombinant hirudin, andthrombin. Examples of such cytostatic or antiproliferative agentsinclude angiopeptin, angiotensin converting enzyme inhibitors such ascaptopril, cilazapril or lisinopril, calcium channel blockers (such asnifedipine), colchicine, fibroblast growth factor (FGF) antagonists,fish oil (ω-3-fatty acid), histamine antagonists, lovastatin (aninhibitor of HMG-CoA reductase, a cholesterol lowering drug), monoclonalantibodies (such as those specific for Platelet-Derived Growth Factor(PDGF) receptors), nitroprusside, phosphodiesterase inhibitors,prostaglandin inhibitors, suramin, serotonin blockers, steroids,thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist), andnitric oxide. An example of an antiallergic agent is permirolastpotassium. Other therapeutic substances or agents which may beappropriate include alpha-interferon, genetically engineered epithelialcells, rapamycin, derivatives and analogs of rapamycin, estradiol,clobetasol, and dexamethasone. Functional derivatives or structuralanalogs of the aforementioned drugs can also be used, such as anysuitable derivative of rapamycin.

PArg can be synthesized as a dendritic (branched to a large degree)polymer which can fully envelop and thus host the active substance, moreparticularly cationic agents, leading to synergistic effects. Examplesof the biologically active substances suitable of being hosted by PArgin the dendritic form include silver cation and sulfonyl amide.

The coatings and methods of the present invention have been describedwith reference to a stent, such as a balloon expandable orself-expandable stent. The use of the coating is not limited to stents,however, and the coating can also be used with a variety of othermedical devices. Examples of implantable medical devices that can beused in conjunction with the embodiments of this invention includestent-grafts, grafts (e.g., aortic grafts), artificial heart valves,cerebrospinal fluid shunts, pacemaker electrodes, axius coronary shuntsand endocardial leads (e.g., FINELINE and ENDOTAK, available fromGuidant Corporation). The underlying structure of the device can be ofvirtually any design. The device can be made of a metallic material oran alloy such as, but not limited to, cobalt-chromium alloys (e.g.,ELGILOY), stainless steel (316L), “MP35N,” “MP20N,” ELASTINITE, Nitinol,tantalum, tantalum-based alloys, nickel-titanium alloy, platinum,platinum-based alloys such as, e.g., platinum-iridium alloy, iridium,gold, magnesium, titanium, titanium-based alloys, zirconium-basedalloys, or combinations thereof. Devices made from bioabsorbable orbiostable polymers can also be used with the embodiments of the presentinvention.

“MP35N” and “MP20N” are trade names for alloys of cobalt, nickel,chromium and molybdenum available from Standard Press Steel Co. ofJenkintown, Pa. “MP35N” consists of 35% cobalt, 35% nickel, 20%chromium, and 10% molybdenum. “MP20N” consists of 50% cobalt, 20%nickel, 20% chromium, and 10% molybdenum.

Embodiments of the present invention can be further illustrated by thefollowing set forth examples.

EXAMPLE 1

A first composition can be prepared by mixing the following components:

(a) between about 1.0 mass % and about 15 mass %, for example, about 2.0mass % of EVAL; and

(b) the balance, DMAC solvent.

The first composition can be applied onto the surface of a bare 13 mmTETRA stent (available from Guidant Corporation) by spraying and driedto form a primer layer. A spray coater can be used, having a 0.014 fannozzle maintained at about 60° C. with a feed pressure of about 0.2 atm(about 3 psi) and an atomization pressure of about 1.3 atm (about 20psi). About 70 μg of the wet coating can be applied. The primer can bebaked at about 140° C. for about 2 hours, yielding a dry primer layer.

A second composition can be prepared by mixing the following components:

(c) between about 1.0 mass % and about 15 mass %, for example, about 1.7mass % of EVAL;

(d) between about 0.05 mass % and about 2.0 mass %, for example, about0.7 mass % of R7; and

(e) the balance, a solvent mixture, comprising i-propanol (IPA),distilled water and DMAC in a ratio IPA:H₂O:DMAC of about 1:4:33.

The second composition can be applied onto the dried primer layer toform a first sub-layer of the drug-polymer layer, using the samespraying technique and equipment used for applying the primer layer.About 200 μg of the wet coating can be applied, followed by drying,e.g., by baking as described above.

A third composition, a suspension of R7, can be prepared by mixing thefollowing components:

(f) between about 1.0 mass % and about 15 mass %, for example, about 1.6mass % of EVAL;

(g) between about 0.05 mass % and about 2.0 mass %, for example, about0.3 mass % of R7; and

(h) the balance, a solvent mixture, comprising i-propanol (IPA),distilled water and DMAC in a ratio IPA:H₂O:DMAC of between about 3:1:12and 6:1:25.

The suspension composition can be applied onto the dried first sub-layerof the drug-polymer layer, to complete forming the drug-polymer layer,using the same spraying technique and equipment used for applying theprimer layer and the first sub-layer of the drug-polymer layer. About200 μg of the suspension can be applied, followed by drying, e.g., bybaking as described above.

A fourth composition can be prepared by mixing the following components:

(i) between about 1.0 mass % and about 15 mass %, for example, about 2.0mass % of PBMA; and

(j) the balance, a mixture of solvents, xylene, FLUX REMOVER AMS, andacetone in a ratio of about 25:19:5 by mass.

The fourth composition can be applied onto the dried drug-polymer layer,to form a topcoat layer, using the same spraying technique andequipment. About 100 μg of the wet coating can be applied, followed bydrying, e.g., by baking as described above.

A fifth composition can be prepared by mixing the following components:

(k) between about 1.0 mass % and about 15 mass %, for example, about 2.0mass % of PBMA; and

(l) between about 0.05 mass % and about 2.0 mass %, for example, about0.7 mass % of R7; and

(m) the balance, a mixture of solvents, xylene, FLUX REMOVER AMS, andacetone in a ratio of about 25:19:5 by mass.

The fifth composition can be applied onto the dried topcoat layer, toform a finishing coat layer, using the same spraying technique andequipment used for applying the primer, the drug-polymer, and thetopcoat layers. About 100 μg of the wet coating can be applied, followedby drying, e.g., by baking as described above.

EXAMPLE 2

A coating comprising a primer layer and a drug-polymer layer can beapplied onto a stent, as described in steps (a) through (h) ofExample 1. The stent can be placed in a humidifying chamber, at thetemperature of about 50° C. and a relative humidity of about 100%, forabout 24 hours. A topcoat composition can be prepared by mixing thefollowing components:

(a) between about 1.0 mass % and about 15 mass %, for example, about 2.0mass % of PBMA; and

(b) the balance, a mixture of solvents, xylene, FLUX REMOVER AMS, andacetone in a ratio of about 25:19:5 by mass.

The stent can be removed from the humidifying chamber and dried. Thetopcoat composition can then be applied onto the drug-polymer layer, toform a topcoat layer, using the same spraying technique and equipment asdescribed in Example 1. About 100 μg of the wet coating can be applied,followed by drying, e.g., by baking as described above.

EXAMPLE 3

A stent coating can be made as described in Example 1, except instead ofR7, poly(L-arginine) having weight-average molecular weight of about5,000 is used. For this kind of PArg, p=29. The coated stent can be thensubjected to an electronic beam having an energy of about 2.5 MRad forabout 1 second.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

1. A method for fabricating a coating for an implantable medical device,comprising: (a) forming a coating on the device, the coating including apolycationic peptide; and (b) treating the coating with a stimulus thatcleaves peptide bonds for enriching a region close to the outer surfaceof the coating with the polycationic peptide.
 2. The method of claim 1,wherein the implantable medical device is a stent.
 3. The method ofclaim 1, wherein the polycationic peptide includes poly(L-arginine),poly(D-arginine), poly(D,L-arginine), poly(L-lysine), poly(D-lysine),poly(δ-guanidino-α-aminobutyric acid), and a mixture of poly(L-arginine)and poly(D-arginine).
 4. The method of claim 1, wherein the treating ofthe coating includes subjecting the device to a humid environment at aselected temperature.
 5. The method of claim 4, wherein the temperatureis about 50° C. and the humidity is about 100%.
 6. The method of claim1, wherein the treating includes subjecting the device to an electronicbeam or to autoclaving.
 7. The method of claim 6, wherein the electronicbeam has energy of about 2.5 MRad.
 8. A coating for an implantablemedical device, the coating comprising two regions, a first regionincluding a polycationic peptide and a second region free from thepolycationic peptide, wherein the polycationic peptide is encapsulatedin particles in the coating.
 9. The coating of claim 8, wherein theregion free from the polycationic peptide is positioned on the surfaceof the device and beneath the region including the polycationic peptide.10. The coating of claim 8, wherein the particles are fabricated of asubstance selected from a group consisting of poly(glycolic acid),poly(D-lactic acid), poly(L-lactic acid), poly(butyleneterephtalate-co-ethylene glycol) and mixtures thereof.
 11. A method ofmodifying a coating for an implantable medical device, the coatingincluding a polycationic peptide, comprising exposing the coating toethylene oxide at a selected temperature and conjugating poly(ethyleneglycol) to the coating.
 12. A method of fabricating a coating for amedical device, comprising forming a coating on the device, the coatingincluding a polycationic peptide, and causing some of the peptide bondsin the polycationic peptide to be cleaved, whereby the population offree peptides in the coating is increased.
 13. The method of claim 11,wherein the polycationic peptide includes poly(L-arginine),poly(D-arginine), poly(D,L-arginine), poly(L-lysine), poly(D-lysine),poly(δ-guanidino-α-aminobutyric acid), and a mixture of poly(L-arginine)and poly(D-arginine).
 14. The method of claim 11, wherein the device isa stent.
 15. The method of claim 12, wherein the polycationic peptideincludes poly(L-arginine), poly(D-arginine), poly(D,L-arginine),poly(L-lysine), poly(D-lysine), poly(δ-guanidino-α-aminobutyric acid),and a mixture of poly(L-arginine) and poly(D-arginine).
 16. The methodof claim 12, wherein the device is a stent.
 17. A method of fabricatinga coated stent, comprising forming a coating comprising two regions onthe stent wherein the coating includes a first region containing apeptide and a second region free from the peptide wherein the peptide isencapsulated in particles in the coating.
 18. A coating for a medicaldevice comprising a peptide that has been cleaved such that thepopulation of the peptide is greatest at the outmost region of thecoating.
 19. The coating of claim 8, wherein the implantable medicaldevice is a stent.
 20. The coating of claim 8, wherein the polycationicpeptide includes poly(L-arginine), poly(D-arginine), poly(D,L-arginine),poly(L-lysine), poly(D-lysine), poly(δ-guanidino-α-aminobutyric acid),and a mixture of poly(L-arginine) and poly(D-arginine).
 21. The methodof claim 17, wherein the implantable medical device is a stent.
 22. Themethod of claim 17, wherein the polycationic peptide includespoly(L-arginine), poly(D-arginine), poly(D,L-arginine), poly(L-lysine),poly(D-lysine), poly(δ-guanidino-α-aminobutyric acid), and a mixture ofpoly(L-arginine) and poly(D-arginine).